Brand name: Duvyzat
Drug class: Other Miscellaneous Therapeutic Agents

Medically reviewed by Drugs.com on Dec 10, 2024. Written by ASHP.

Introduction

Histone deacetylase (HDAC) inhibitor.¹

Uses for Givinostat Hydrochloride

Duchenne Muscular Dystrophy

Treatment of Duchenne muscular dystrophy (DMD) in patients ≥6 years of age.^{1 3 7} Designated an orphan drug by FDA for this use.²

Current standard of care for patients with DMD is the use of corticosteroids for improving muscle strength and function.^{4 5 6} Antisense oligonucleotide therapies also are available for treatment of a subset of patients with DMD caused by mutations amenable to exon skipping.⁷ Givinostat is a non-steroid oral therapy that may provide a treatment option for a broad population of patients with DMD not limited by genetic subtype.⁷

Givinostat Hydrochloride Dosage and Administration

General

Pretreatment Screening

• Obtain and evaluate baseline platelet counts.¹ Do not initiate givinostat in patients with a platelet count <150,000/mm³.¹

• Obtain and evaluate triglycerides.¹

• Obtain an ECG prior to initiating treatment in patients with underlying cardiac disease or in patients taking concomitant medications that cause QT prolongation.¹

Patient Monitoring

• Monitor triglycerides as recommended during treatment to determine if dosage modifications are needed. ¹ Monitor triglycerides at 1, 3, and 6 months; continue to monitor every 6 months thereafter.¹

• Monitor blood counts every 2 weeks for the first 2 months of treatment; continue to monitor monthly for the first 3 months, and then every 3 months thereafter. ¹

Administration

Oral Administration

Administer orally as a suspension.¹

Administer recommended dose twice daily with food.¹

Before use, shake the suspension for at least 30 seconds by inverting the bottle by 180° until homogenous solution is observed. ¹

Using provided graduated oral syringe, measure and administer appropriate volume of suspension corresponding to the prescribed dose.¹

Discard any unused oral suspension remaining after 60 days of first opening the bottle.¹ Do not throw away the oral syringe; store in a clean, dry place.¹

If a dose is missed, skip missed dose and take next dose as scheduled; do not take double or extra doses.¹

Dosage

Pediatric Patients

Duchenne Muscular Dystrophy

Oral

Recommended dosage in pediatric patients ≥6 years of age is based on actual body weight as follows:¹

For patients weighing 10 to <20 kg, recommended dosage is 22.2 mg twice daily (2.5 mL twice daily of the oral suspension).¹

For patients weighing 20 to <40 kg, recommended dosage is 31 mg twice daily (3.5 mL twice daily of the oral suspension).¹

For patients weighing 40 to <60 kg, recommended dosage is 44.3 mg twice daily (5 mL twice daily of the oral suspension).¹

For patients weighing ≥60 kg, recommended dosage is 53.2 mg twice daily (6 mL twice daily of the oral suspension).¹

Adults

Duchenne Muscular Dystrophy

Oral

Recommended dosage is based on actual body weight as follows:¹

For patients weighing 10 to <20 kg, recommended dosage is 22.2 mg twice daily (2.5 mL twice daily of the oral suspension).¹

For patients weighing 20 to <40 kg, recommended dosage is 31 mg twice daily (3.5 mL twice daily of the oral suspension).¹

For patients weighing 40 to <60 kg, recommended dosage is 44.3 mg twice daily (5 mL twice daily of the oral suspension).¹

For patients weighing ≥60 kg, recommended dosage is 53.2 mg twice daily (6 mL twice daily of the oral suspension).¹

Dosage Modification for Adverse Effects

Dosage modification may be required if the following occurs: platelet count <150,000/mm³ verified in 2 assessments 1 week apart; moderate or severe diarrhea; or fasting triglycerides >300 mg/dL verified by 2 assessments 1 week apart.¹

See Table 1 for the first dosage modification.¹ If adverse effects persist after first dosage modification, proceed to second dosage modification (see Table 2).¹ If adverse reaction persists after second dosage modification, discontinue givinostat therapy.¹

Based on severity of these adverse reactions, consider treatment interruption prior to dosage modifications. ¹

Special Populations

Hepatic Impairment

No specific dosage recommendations.¹

Renal Impairment

No specific dosage recommendations.¹

Geriatric Patients

No specific dosage recommendations.¹

Cautions for Givinostat Hydrochloride

Contraindications

• None.¹

Warnings/Precautions

Hematological Changes

Givinostat can cause dose-related thrombocytopenia and other signs of myelosuppression, including decreased hemoglobin and neutropenia. ¹ Thrombocytopenia has been associated with bleeding events including epistaxis, hematoma, or contusions.¹

Monitor blood counts every 2 weeks for the first 2 months of treatment; continue to monitor monthly for the first 3 months, and then every 3 months thereafter.¹

Modify dosage if thrombocytopenia occurs.¹ Permanently discontinue treatment if abnormalities worsen despite dosage modification.¹

If signs or symptoms of thrombocytopenia occur, obtain a platelet count as soon as possible, and withhold dosing until platelet count is confirmed.¹

Increased Triglycerides

Givinostat can cause elevations in triglycerides.¹

Monitor triglycerides at 1, 3, and 6 months; continue to monitor every 6 months thereafter.¹ Modify dosage if fasting triglycerides >300 mg/dL.¹

Discontinue treatment if triglycerides remain elevated despite adequate dietary intervention and dosage adjustment.¹

GI Disturbances

Givinostat can cause GI abnormalities (e.g., diarrhea, nausea, vomiting, abdominal pain).¹

Consider administering antiemetics or antidiarrheal medications during treatment with givinostat.¹

Replace fluids and electrolytes as needed to prevent dehydration.¹

Modify dosage of givinostat in patients with moderate to severe diarrhea; discontinue treatment if significant symptoms persist.¹

QT Prolongation

Risk of QTc interval prolongation.¹ Avoid use in patients who are at an increased risk for ventricular arrhythmias (including torsades de pointes), such as those with congenital long QT syndrome, coronary artery disease, electrolyte disturbances, or receiving concomitant drugs known to cause QT prolongation.¹

Obtain ECGs prior to initiating treatment in patients with underlying cardiac disease or in patients who are taking concomitant medications that cause QT prolongation.¹

Specific Populations

Pregnancy

Givinostat is indicated for the treatment of DMD, which is a disease of predominantly young male patients.¹ Therefore, there are no adequate data in pregnant women.¹ In animal studies, decreased fetal body weight, increased structural variations, increased embryofetal and offspring mortality and neurobehavioral changes observed.¹

Lactation

Not known whether givinostat is present in human milk or if the drug has any effects on the breastfed infant or on milk production.¹ Consider developmental and health benefits of breastfeeding along with the mother's clinical need for givinostat and any potential adverse effects on the breastfed infant from the drug or underlying maternal condition.¹

Females and Males of Reproductive Potential

No data available on the effect of givinostat on reproductive potential.¹ Animal studies indicate possible adverse effects on reproduction.¹

Pediatric Use

Safety and effectiveness in pediatric patients <6 years of age not established.¹

Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no experience in geriatric patients.¹

Hepatic Impairment

Pharmacokinetics not studied.¹ Because givinostat is eliminated mainly through hepatic metabolism, hepatic impairment may increase drug exposure.¹

Renal Impairment

Pharmacokinetics not studied; however, renal impairment not expected to affect exposure to givinostat because the drug is not significantly eliminated renally.¹

Common Adverse Effects

Most common adverse reactions (≥10%): diarrhea, abdominal pain, thrombocytopenia, nausea/vomiting, hypertriglyceridemia, pyrexia.¹

Drug Interactions

Not metabolized by CYP enzymes and uridine diphosphate glucuronosyltransferase (UGT).¹

Substrate of intestinal transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).¹ Potential to inhibit intestinal transporter P-gp (MDR1) and BCRP leading to non-clinically meaningful interactions.¹

Induces CYP1A2, 2B6, and CYP3A4.¹

Weak intestinal CYP3A4 inhibitor; also a weak inhibitor of the renal uptake transporter OCT2.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Givinostat has a weak inhibition of the intestinal CYP3A4 enzyme.¹

CYP3A4 sensitive substrates: closely monitor patients when givinostat is used concomitantly with orally administered CYP3A4 sensitive substrates for which a small change in substrate plasma concentration may result in serious toxicities.¹

CYP isoenzyme inducers or inhibitors: systemic exposure of givinostat not likely to be significantly affected.¹

Drugs Affecting or Affected by Transport Systems

Strong P-gp inhibitors: weak effect on givinostat pharmacokinetics expected.¹

Drugs Associated with QT Prolongation

May result in increase in QTc interval and adverse reactions, including torsade de pointes, other serious arrhythmias, and sudden death.¹

If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated.¹ Withhold givinostat therapy if QTc interval >500 msec or change from baseline is >60 msec.¹

Givinostat Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Exhibits linear pharmacokinetics with systemic exposure dose-proportional across therapeutic dose range.¹ An accumulation of <2-fold observed after twice daily administration.¹

Time to peak plasma concentrations is 2 to 3 hours after oral administration.¹

Food

Administration with high fat standard meal increased exposure by about 40% and increased peak plasma concentrations by about 23%; delayed time to peak concentration from 2 to 3 hours.¹

Distribution

Extent

Slightly partitioned into red blood cells.¹

Plasma Protein Binding

About 96%.¹

Elimination

Metabolism

CYP enzymes and UGTs are not involved in main metabolic reactions.¹ Extensively metabolized forming several metabolites; 4 inactive metabolites characterized.¹

Elimination Route

Elimination likely dependent on metabolism followed by renal and biliary excretion of metabolites.¹ Urinary excretion is minimal (<3% of the dose).¹

Half-Life

Elimination half-life is about 6 hours.¹

Special Populations

Body weight may affect pharmacokinetics. ¹ Age has no effect.¹

Stability

Storage

Oral

Suspension

Store at 20-25°C, excursions permitted between 15-30°C.¹ Do not freeze.¹ Store upright.¹ Discard any unused suspension remaining after 60 days of first opening the bottle.¹

Actions

• A histone deacetylase (HDAC) inhibitor.¹

• Exact mechanism of action in DMD unknown;¹ however, intended to work directly on the muscle.⁷ As an HDAC inhibitor, givinostat targets the upregulation of follistatin, which stimulates myogenesis.⁷

Advice to Patients

• Advise patients to read the FDA-approved patient labeling.¹

• Instruct patients or caregivers to shake givinostat oral suspension well before measuring out each dose.¹

• Instruct patients or caregivers to administer givinostat using the provided graduated oral syringe to measure the appropriate volume of suspension corresponding to the prescribed dose for the patient and to take with food.¹

• Instruct patients or caregivers to discard any unused givinostat oral suspension remaining after 60 days of first opening the bottle.¹

• Inform patients and/or caregivers that givinostat can cause hematological changes including a decrease in platelet counts, anemia, and a decrease in neutrophils.¹ Advise patients to notify their healthcare provider if they have any signs or symptoms of these adverse reactions (e.g., easy bruising, excessive bleeding from cuts, blood in the stool, fatigue).¹ Instruct patients to adhere to the testing recommended to monitor for these adverse reactions.¹ Inform patients that their dosage may need to be changed or their treatment may need to be stopped depending on the results of their test for platelet counts.¹

• Inform patients and/or caregivers that givinostat can cause an increase in triglycerides.¹ Instruct patients to adhere to the testing recommended to monitor for this adverse reaction.¹ Inform patients that their dosage may need to be changed or their treatment may need to be stopped depending on the results of their test for triglycerides.¹

• Inform patients and/or caregivers that givinostat can cause diarrhea and vomiting, which may require medication for treatment.¹ Advise patients to maintain hydration if diarrhea or vomiting occurs and contact their healthcare provider if the symptoms persist or become moderate to severe.¹ Inform patients that their dosage may need to be changed or their treatment may need to be stopped depending on the severity of diarrhea.¹

• Inform patients and/or caregivers that givinostat can cause prolongation of the QTc interval.¹ Instruct patients to notify their healthcare provider if they have or develop any symptoms of significant QTc prolongation (e.g., dizziness, lightheadedness, syncope) or new cardiac issues and before taking any over-the-counter (e.g., diphenhydramine), herbal (e.g., echinacea), or prescription medications (e.g., antibiotics).¹

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.¹

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.¹

• Inform patients of other important precautionary information.¹

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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